3-(2-(4-morpholino) ethyl)-1-(5-nitrofurfurylidenamino) hydantoin and acid addition salts thereof



United States Patent 3,075,974 3-(2-(4 MORPHOLINO)ETHYL)-I-(S-NI'IROFURFU- RYLIDENAMINOEIYDANTOHN AND ACKD AD- DITION SALTS THEREOF Julian Getz Michels, Norwich, N.Y., assignor to The glorwich Pharmacal Company, a corporation of New ork N0 Drawing. Filed Dec. 27, 1960, Ser. No. 73,331 2 Claims. (Cl. 260-240) This invention relates to a new chemical compound and acid addition salts thereof which possess a high order of antibacterial activity and which exhibit resistance to metabolic destruction. The compound may be described as a 3-[2-(4 morpholino)ethyl] 1 (S-nitrofurfurylideneamino) hydantoin. The compound and its acid addition salts are represented by the formula:

wherein X represents an acid; and n represent a number from 0-1.

This new compound is a very etfective systemic chemotherapeutic agent when administered per os to animals lethal y infected with highly pathogenic bacteria; for instance, Staphylococcus aureus. Death is prevented in 100% of mice lethally infected with S. aureus by the oral administration, one-half hour post infection, of a single dose of 200 mg./kg. of this new compound. Mice similarly infected but not treated with this compound suffer a mortality of 95%. The extremely high effectiveness of this compound in combatting S. aureus plus its relatively low toxicity renders this compound a very useful chemotherapeutic agent.

It has also been found that this new compound is further distinguished by the high order of coccidiostatic activity which it exhibits in combatting Eimerz'a tcnella infections in poultry when administered in far less than toxic amounts. It may be used prophylactically in the prevention of coccidiosis or as a therapeutic treatment of established disease due to that organism. In the therapeutic treatment -of coccidiosis concentrations of up to about 0.022% by weight, based on the weight of poultry rations, may be used to advantage. When employed prophylactically, a lesser amount in the range of 0.008 to about 0.011% by weight is normally sufficient.

The compound of this invention is remarkably resistant to metabolic processes which frequently cause substantial breakdown and loss of available active agent. When administered to rats, in excess of of the administered dose appears in the urine. This amount renders the urine antibacterial to organisms such as Escherichia coli and S. aureus, frequently encountered and often troublesome in urinary tract infections. The ability possessed by this compound to resist metabolic influences and to provide urinary antibacterial concentrations makes it a valuable urinary tract chemotherapeutic.

This new compound is relatively non toxic. In mice the LD is about 600 mg./kg. Poultry consuming feed containing 0.022% by weight of this new compound show no evidence of toxicity.

The new compound of this invntion is not limited to the oral route of administration for chemotherapeutic purposes. The acid addition salts particularly those formed with physiologically tolerable acids, such as hydrochloric, sulfuric, and phosphoric, are readily soluble in aqueous media. These salts because of their solubility may be readily adapted to the parenteral route of administration, for instance, intravenous, by dissolving them in physiologically acceptable menstrua such as isotonic saline or glucose solution.

The compounding and formulating of 3-[2-(4-morpholino)ethyl]-1-(5 nitrofurfurylideneamino)hydantoin in dosage forms such as tablets, suspensions, elixirs, syrups, lozenges and the like is readily carried out using those excipients and adjuvants commonly employed in pharmaceutical practice.

The preparation of this new compound and its acid ad dition salts may be readily carried out in a number of ways. The method which is currently preferred consists in reacting a solution comprising a salt of a l-aralkylideneaminohydantoin in an organic solvent with morpholinoethyl chloride to produce a 3-morpholinoethyl-l-aralkylideneaminohydantoin; followed by treatment of this product to release the 3-morpholinoethyl-l-aminohydantoin which is then condensed with S-nitrofurfural or a derivative thereof capable of supplying it under the reaction conditions.

More specifically, a solution of sodium l-benzylideneaminohydantoin in dimethylformamidereacts readily under the influence of heat with morpholinoethyl chloride to yield 3-morpholinoethyl-1-benzylideneaminohydantoin. Removal of the dimethylformamide followed by steam distillation of the residue in the presence of an aqueous mineral acid, i.e., hydrochloric, to remove the benzaldehyde and to release the 3-morpholinoethyl-1-aminohydantoin for reaction with S-nitrofurfural, produces 3-[2- (4-morpholino)ethyl]-1-(5 nitrofurfurylideneamino)by dantoin in excellent yield.

In order that this invention may be more readily available to those skilledin the art, the following illustrative example is hereby submitted.

EXAMPLE I 3-[2-(4-M0rph0lino)Ethyl]-1-(5-Nitr0furfurylideneamino) H ydantoin Hydrochloride A solution of 23.5 g. of l-benzylideneaminohydantoin in 600 cc. of dimethylformamide is treated with 5.1 g. of sodium hydride in mineral oil. When the reaction is complete, 17.3 g. of morpholinoethyl chloride is added and the mixture heated at -115 C. The dimethylformamide is distilled ofi. under reduced pressure and the residue steam distilled in the presence of hydrochloric acid. When no more benzaldehyde is evolved, a solution of 20 g. of S-nitro-furfural in alcohol is added. The hydrochloride salt of 3-[2-(4morpholino)ethylJ-l-(S-nitrofurfurylideneamino)hydantoin precipitates and is filtered (31.1 g., 69%). This is recrystallized from water using charcoal to clarify. Further recrystallization to remove any impurity is conducted from aqueous acetone. There is obtained 15.6 g. of purified product having a melting point of 225 C. with decomposition. The free base is prepared by treating an aqueous solution of the salt with sodium bicarbonate.

Patented Jan. 29, 1963 3 4 In lieu of S-nitrofurfural, S-nitrofurfural diacetate may 2. 3-[2 (4morpholino)ethyl]-l-(5 znitrofurfurylidenebe used. amino)hydantoin hydrochloride represented by the What is claimed is: formula:

1. A compound having chemotherapeutic activity and resistance to metabolic destruction selected from the 5 group consisting of a base and pharmaceutically accept- JL able acid addition salts of the formula: 0 CH=N N"C=O CHFCH -GH:CH2N\ O .HCl I l H:CC/ CRTs-C O =N V 0 QH=N-N -C:0 Di -CH4 10 NCH1CHr-.N '0 X1; References Cited .in the file of this patent Hie-d CHz-Gfi, UNITED "STATES PATENTS Whlch 2,610,181 Hayes Sept. 9, 1952 Xrepresents amineral-acid; and 15 2,802,002 Gever Aug. 6, 1957 n represents a number from 0-1. 2,990,402 Jack et -al. June 27, 1961 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Pa-tent No. 3,075,974 January 29, 1963 Julian Getz Michels It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 3, for "invntion" read invention line 57, for (Qmorpholino) read (4morpholino) column 3, lines 8 to 13, the formula should appear as shown below instead of as in the patent: 1

column 4, lines 5 to 9,, the forumla should appear as shown below instead of as in the patent:

- 4 2 2 n c-o cH ---ca Signed and sealed this 27th day of August 1963.

(SEAL) Attest:

ERNEST w. SWIDER DAVll 3 L LADD Attesting Officer Commissioner of Patents 

1. A COMPOUND HAVING CHEMOTHERAPEUTIC ACTIVITY AND RESISTANCE TO METABOLIC DESIRATION SELECTED FROM THE GROUP CONSISTING OF A BASE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OD THE FORMULA: 